Relative non-steroidal anti-inflammatory drug (NSAID) antiproliferative activity is mediated through p21-induced G1 arrest and E2F inhibition

Jonathan M Bock; Sarita G Menon; Prabhat C Goswami; Lori L Sinclair; Nichole S Bedford; Frederick E Domann; Douglas K Trask

doi:10.1002/mc.20318

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Relative non-steroidal anti-inflammatory drug (NSAID) antiproliferative activity is mediated through p21-induced G1 arrest and E2F inhibition

Journal article

Peer reviewed

Relative non-steroidal anti-inflammatory drug (NSAID) antiproliferative activity is mediated through p21-induced G1 arrest and E2F inhibition

Jonathan M Bock, Sarita G Menon, Prabhat C Goswami, Lori L Sinclair, Nichole S Bedford, Frederick E Domann and Douglas K Trask

Molecular carcinogenesis, Vol.46(10), pp.857-864

10/2007

DOI: 10.1002/mc.20318

PMID: 17415779

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Abstract

This study was performed to compare the relative antineoplastic activity of 10 different non-steroidal anti-inflammatory drugs (NSAIDs) in clinical use, and to investigate the underlying mechanisms of this activity in a squamous cell carcinoma of the head and neck model (SCCHN). A standard 5-day MTT assay was used to calculate IC(50) values in UM-SCC-1 cells for 10 NSAIDs, including celecoxib, rofecoxib, sulindac sulfide, sulindac sulfone, indomethacin, ketoprofen, flurbiprofen, naproxen, piroxicam, and aspirin. Celecoxib, a COX-2 specific inhibitor, was by far the most potent NSAID, with an IC(50) of 39.9 +/- 1.1 microM, followed by sulindac sulfide (116.5 +/- 2.34 microM). Celecoxib and sulindac sulfide also induced more activation of caspase-3 than any other NSAID. Cell cycle analysis showed that celecoxib and sulindac sulfide both induced a 3-fold increase in G(1) phase distribution, and this correlated with strong induction of p21(waf1/cip1), inhibition of cyclin D1, and hypophosphorylation of Rb. Celecoxib and sulindac sulfide treatment induced strong downstream inhibition of E2F transactivating activity as determined by a luciferase reporter assay. These data demonstrate the wide range of activity of various NSAID agents, and reveal a mechanism of action through cell cycle inhibition and induction of apoptosis.

Cyclin-Dependent Kinase Inhibitor p21 - pharmacology

Humans

Celecoxib

G1 Phase - drug effects

Sulfonamides - pharmacology

Anti-Inflammatory Agents, Non-Steroidal - pharmacology

Sulindac - analogs & derivatives

E2F Transcription Factors - antagonists & inhibitors

Cell Proliferation - drug effects

Tumor Cells, Cultured

Sulindac - pharmacology

Apoptosis

Pyrazoles - pharmacology

Details

Title: Subtitle: Relative non-steroidal anti-inflammatory drug (NSAID) antiproliferative activity is mediated through p21-induced G1 arrest and E2F inhibition
Creators: Jonathan M Bock - Department of Otolaryngology--Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
Sarita G Menon
Prabhat C Goswami
Lori L Sinclair
Nichole S Bedford
Frederick E Domann
Douglas K Trask
Resource Type: Journal article
Publication Details: Molecular carcinogenesis, Vol.46(10), pp.857-864
Publisher: United States
DOI: 10.1002/mc.20318
PMID: 17415779
ISSN: 0899-1987
eISSN: 1098-2744
Grant note: P01 CA66081 / NCI NIH HHS R01 CA111365 / NCI NIH HHS K08 CA104361 / NCI NIH HHS
Language: English
Date published: 10/2007
Academic Unit: Pathology; Surgery; Radiation Oncology
Record Identifier: 9984046819502771

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